Original Articles
Role and regulation of cyclooxygenase-2 during inflammation

https://doi.org/10.1016/S0002-9343(99)00115-1Get rights and content

Abstract

Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase (COX) and subsequent downstream synthetases. Recently, it has been found that there are two closely related forms of COX, which are now known as COX-1 and COX-2. Although both isoforms of this enzyme convert arachidonate to prostaglandins, there are significant differences in their distribution in the body and their roles in health and disease. The basis for these important differences lies in the genes for COX-1 and COX-2 and the regulation of these genes.

COX-1, the predominantly constitutive form of the enzyme, is expressed throughout the body and provides certain homeostatic functions, such as maintaining normal gastric mucosa, influencing renal blood flow, and aiding in blood clotting by abetting platelet aggregation. In contrast, COX-2, the inducible form, is expressed in response to inflammatory and other physiologic stimuli and growth factors and is involved in the production of those prostaglandins that mediate pain and support the inflammatory process.

All conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit both COX-1 and COX-2 at standard anti-inflammatory doses. The beneficial anti-inflammatory and analgesic effects occur through the inhibition of COX-2, but the gastrointestinal toxicities and the mild bleeding diathesis occur as a result of concurrent inhibition of COX-1. It is important that physicians fully understand the pharmacologic basis for the differential actions of NSAIDs when prescribing them for pain and inflammation. This understanding is also important so that physicians can critically evaluate the basis for, and the emerging data on, COX-2–specific inhibitors and their potential role in clinical medicine. Agents that would inhibit COX-2 while sparing COX-1 represent an attractive therapeutic development and could represent a major advance in the treatment of rheumatoid arthritis and osteoarthritis, as well as a diverse array of other conditions.

Section snippets

Basic biochemistry of prostaglandins and their formation

Prostaglandins, the first metabolites of arachidonic acid to be characterized, mediate several key physiologic functions. The formation of prostaglandins begins when arachidonic acid is liberated from phospholipids in the cell membrane by the action of phospholipase A2. At least two separate enzymatic pathways exist for the conversion of arachidonic acid to physiologically important metabolites. In the first, cyclooxygenase (COX) initiates the formation of prostaglandins and thromboxane.

Evidence demonstrating COX-2 selectivity

The issue of COX selectivity of various inhibitors must be defined both in vitro and in vivo, and various experimental systems generate different data. Experimental paradigms may include in vitro cell-free recombinant enzymes, whole-cell preparations, or in vivo models. Investigators at different laboratories may thus produce widely divergent data demonstrating COX-2 selectivity. Further variability is introduced in human studies, in which drugs must be administered at sufficient strengths to

The role of prostaglandins in mediating pain and inflammation

The role of prostaglandins formed by COX-2 in mediating pain, and the inhibitory effects of NSAIDs on this reaction, can be demonstrated in animal models.7 In one such model of acute inflammation and pain, an irritant, carrageenan, is injected into the paw of a rat and paw volume is measured as edema develops.8, 9 In this model, hyperalgesia develops in the injected paw concurrent with the edema. Experimental agents may be evaluated for anti-inflammatory and analgesic activity by administering

Biochemical basis for the distinction between COX-1 and COX-2 and the clinical implications

Although intellectually provocative and medically intriguing, the above discussion does not provide a molecular basis for understanding why some agents and not others demonstrate COX-1/COX-2 selectivity in these model systems. The explanation for the fundamental differences in the structures of the COX isoforms and their roles in the body lay in their respective genes, which occur on two different chromosomes.12

The COX-2 gene contains regions that are characteristic of early response genes and

Conclusions

Cyclooxygenase has been shown to exist in two distinct forms. These isoforms have diverse physiologic and pathophysiologic roles and exhibit pharmacologically important differences in structure and their profiles of inhibition. With the advent of good in vitro assay systems and animal models of pain and inflammation, efforts have turned to the development of potential therapeutic agents that can specifically inhibit COX-2 while sparing COX-1. The in vitro selectivity of investigational agents,

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